Alzheimer's disease (AD) is the most common type of dementia in the elderly. In the 1990s, about 15 million people suffered from AD (Hebert L. E., Scherr P. A., Beckett L. A. et al.; J. Am. Med. Assoc. 1995, 273, 1354-1359), and WHO estimates that if current trends persist, this number will double by 2020 (Dufouil C., Alperovitch A.; Rev. Prat. 2005, 55, 1869-1878). The disease symptoms are cognitive and behavioral dysfunctions and progressive memory loss.
Despite very intensive research, there is no effective causal therapy of AD so far, and the treatment focuses only on the relief of symptoms. One of the leading therapeutic strategies is based on the assumption that increasing the amount of the neurotransmitter acetylcholine, leads to a better use of the cholinergic neurons, which in turn slows down the progression of the disease. This objective can be achieved by inhibition of acetylcholinesterase (Bartus R. T., Dean R. L., Beer B. et al.; Science 1982, 217, 408-417). Recently, it became clear that butyrylocholinesterase also participates in the control of neurotransmission. In a healthy brain acetylocholinesterase accounts for 80% of the total cholinesteric activity. In case of people suffering from AD, its activity drops to about 60% of the initial value, while increasing the role of butyrylcholinesterase (Greig N. H., Utsuki T., Yu Q. S.; Curr. Med. Res. Opin. 2001, 17, 159-165). It seems therefore, that a strategy aimed at inhibiting the activity of butyrylcholinesterase or both enzymes simultaneously can produce much better therapeutic effects.
The characteristic changes in the brain of AD patients are β-amyloid plaques and neurofibrillary tangles, accompanied by neurodegeneration. Also, large quantities of cholinesterases, in particular butyrylcholinesterase, can be found in both β-amyloid plaques and neurofibrillary tangles (Guillozet A. L. Smiley J. F., Mash D. C. et al.; Ann. Neurol. 1997, 42, 909-918). Therefore cholinesterases may be involved in the formation of plaques and tangles and additionally enhance their toxicity, activating the microglia and hydrolyzing acetylcholine (Greig N. H., Utsuki T., Yu Q. S.; Curr. Med. Res. Opin. 2001, 17, 159-165).
It thus appears that the inhibition of cholinesterases can not only improve the functioning of damaged cholinergic system, but can also prevent its further degeneration.
The compounds used so far in symptomatic treatment of the Alzheimer's disease are tacrine, withdrawn from the market due to serious side effects, and later less toxic compounds of the same mechanism of action, among them donepezil, rivastigmine and galanthamine. These compounds differ in the specifity of action; donepezil inhibits only acetylcholinesterase while rivastigmine acts against both enzymes, exhibiting thus a higher efficiency.
In the last ten years, the research of the new cholinesterase inhibitors expanded to include a group called hybrid drugs—compounds combining in their structures two fragments, a known drug and its copy or two different drugs. These hybrid structures exhibit much higher activity compared to their ‘non-hybrid’ precursors, often showing a synergistic effect of the action.
The publication of the international patent application WO 2004/032929 discloses compounds containing in their structure the tetrahydroacridine ring, acting as dual site acetylcholinesterase inhibitors, especially useful in treatment of cognitive disorders as senile dementia, cerebrovascular dementia, mild cognition impairment, attention deficit disorder, and/or neurodegenerative dementing disease with aberrant protein aggregations as specially Alzheimer's disease, Parkinson disease, ALS, or prion diseases, as Creutzfeldt-Jakob disease or Gerstmann-Straussler-Scheinher disease. Among the compounds disclosed, there are structures containing tetrahydroacridine ring, of which the amine group is connected with the benzene ring of indanone or indanodione through an alkyl linker, possibly containing amine or amide groups.
Oxidative stress is another important factor involved in the neurodegenerative diseases. Therefore, use of the compounds exhibiting antioxidative properties can have a beneficial effect (Floyd R. A., Hensley K., Neurobiol. Aging 2002, 23, 795-807). One of the important antioxidants of well documented activity is the endogenous melatonin (Reiter R. J. et al, Acta. Biochim. Pol. 2003, 50, 1129-1146).
The conception of combining the melatonin (N-acetyl-5-methoxytryptamine) and tetrahydroacridine units was explored in the works of Rodriguez-Franco M. I. and coworkers (J. Med. Chem. 2006, 49, 459-462 and Chem. Med. Chem. 2009, 4, 828-841), who developed hybrid compounds containing amide linkage. These compounds, which are 2-(1H-indol-3-yl)ethyl esters of [(1,2,3,4-tetrahydroacridin-9-ylamino)alkyl]-carbamate acid, disclosed also in the publication of the international patent application WO 2005/005413, exhibit the activity towards inhibition of cholinesterases and additionally have antioxidant properties and prevent the Aβ (β-amyloid) aggregation, therefore acting as neuroprotectors.
Authors of the present invention demonstrated in their previous works (Siwicka A., Molda Z., Wojtasiewicz K., Zawadzka A., Maurin J. K., Panasiewicz M., Pacuszka T., Czarnocki Z.; J. Pineal Research 2008, 45, 40-49 and Molda Z., Wojtasiewicz K., Panasiewicz M., Czarnocki Z.; J. Pineal Research 2010, 49, 55-59) that the phenyl- and alkyl-carbamate derivatives of melatonin and products of its oxidation with singlet oxygen exhibit cholinesterase inhibitory activity.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.